Professor of Genome Biology of Neurodegenerative diseases at the Hertie Institute for Clinical Brain Research in Tübingen & visiting researcher at RIKEN Center for Life Science Technologies, Yokohama, Japan

Areas of investigation/research focus

The underlying causes for neurodegenerative disease are still largely unknown but there is clear evidence that genetic risk factors play an important role. The identification of such genetic risk factors provides us with important starting points to study the molecular processes that lead to disease as they act at the very beginning of the disease process.

Finding new genetic risk factors

To identify new genetic risk factors we investigate families with neurodegenerative diseases as well as large cohorts of sporadic cases using SNP array genotyping and Massive Parallel Sequencing (MPS) approaches such as whole exome and whole genome sequencing. Prof. Heutink is currently is a member of the International Parkinsons Disease Genomics Consortium (IPDGC) and the International FTD genetics Consortium.

The data analysis is performed in close collaboration with Dr. Javier Simón-Sánchez who leads the joined research group Genetics and Epigenetics of Neurodegeneration. The research group "Genetics and Epigenetics of Neurodegeneration" has been jointly established at the Department of Neurodegenerative Diseases within the Hertie Institute for Clinical Brain Research (HIH) and the research group Genome Biology at the German Center for Neurodegenerative Diseases (DZNE). The group has a primary interest in the genetics and genomics of neurodegenerative disorders such as Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP) or Frontotemporal Dementias (FTD). The research group "Genetics and Epigenetics of Neurodegeneration" aims to translate the meaning of previous genetic findings into testable biological hypotheses. Thus, we aim to expand previous work on genetic analysis to a more broader bioinformatic focus by integration of GWAS hits and Next Generation Sequencing (NGS) variants derived from whole-exome, targeted re-sequencing and whole genome sequencing approaches, with expression data from RNA sequencing (RNAseq) and Capped Analysis of Gene Expression (CAGE) experiments. This, in combination with the aforementioned epigenetic data, will help to further understand the genetic (or genomic) mechanisms underlying the etiology of various neurodegenerative disorders.

Understanding the biology of genetic risk factors

The identification of new genetic risk factors allows us to investigate the biological consequences of the underlying mutations to the molecular pathways in which they function in human post-mortem brain and cellular models including primary neurons or patient derived induced pluripotent stem (iPS) cells. We use two main approaches to follow up these findings and to study the biological consequences of genetic mutations.

One approach aims to dissect and study the gene networks in which the risk factors are functioning by studying gene expression in patient post-mortem brain and patient derived cell lines such as iPS derived neurons. We aim to model complete transcriptional networks to identify key regulators of the affected pathways. We perform MPS based gene expression analysis for coding and noncoding RNA expression (RNAseq, CAGE) and combine this with epigenetic and proteomic data using integrative bioinformatics analysis. The work is performed in close collaboration with the Dutch Brain Bank and the group of Applied Genomics for Neurodegenerative diseases at the DZNE-Tübingen led by Dr. Patrizia Rizzu and the research group led by Dr. Javier Simón-Sánchez Genetics and Epigenetics of Neurodegeneration.

To validate and extend our findings and to understand the function of identified genes and non-coding RNAs we follow a second approach using cellular models such as neuroblastoma lines and neuronal differentiated patient derived iPS cell in which we can selectively overexpress or silence newly identified genetic risk factors or key regulatory genes and transcripts form identified pathways. This allows us to study the pathways that act downstream of these genes. We use a combination of “read outs” such as gene expression, epigenetic changes and imaging of reporter constructs or cell organelle morphology.

Our iPS based models are either derived from patients blood or fibroblasts or by using CRISPR/Cas9 genome editing. For our gene silencing experiments and cellular screens we use a genome wide lentiviral shRNA library originally developed by the Broad Institute, and CRISPR/Cas9 pooled libraries.